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Tissue engineering of sizeable cell-scaffold constructs is limited by gradients in tissue quality from the periphery toward the center. Because homogenous delivery of oxygen to three-dimensional (3D) cell cultures remains an unsolved challenge, we hypothesized that uneven oxygen supply may impede uniform cellular growth on scaffolds. In this stu...

Tissue engineering of sizeable cell-scaffold constructs is limited by gradients in tissue quality from the periphery toward the center. Because homogenous delivery of oxygen to three-dimensional (3D) cell cultures remains an unsolved challenge, we hypothesized that uneven oxygen supply may impede uniform cellular growth on scaffolds. In this study we challenged static and dynamic 3D culture systems designed for bone tissue engineering applications with a well-growing subclone of MC3T3-E1 preosteoblasts and continuously measured the oxygen concentrations in the center of cell-seeded scaffolds and in the sur-rounding medium. After as little as 5 days in static culture, central oxygen concentrations dropped to 0%. Subsequently, cells died in central regions of the scaffold but not in its periphery, where oxygen levels were *4%. The use of perfusion bioreactors successfully prevented cell death, yet central oxygen con-centrations did not rise above 4%. We conclude that 3D culture in vitro is associated with relevant oxygen gradients, which can be the cause of inhomogeneous tissue quality. Perfusion bioreactors prevent cell death but they do not entirely eliminate 3D culture–associated oxygen gradients. Therefore, we advise continuous oxygen monitoring of 3D culture systems to ensure tissue quality throughout engineered constructs. Minimize

Background: During reperfusion of ischaemic myocardium, Na+/H+ exchange promotes recovery from acidosis resulting in an accumulation of intracellular Na+. This leads to calcium overload via Na+/Ca2+ exchange and might result in cell necrosis contributing to reperfusion injury. Methods and Results: We assessed whether HOE 694, a specific inhib...

Background: During reperfusion of ischaemic myocardium, Na+/H+ exchange promotes recovery from acidosis resulting in an accumulation of intracellular Na+. This leads to calcium overload via Na+/Ca2+ exchange and might result in cell necrosis contributing to reperfusion injury. Methods and Results: We assessed whether HOE 694, a specific inhibitor of Na+/H+ exchange, is able to reduce infarct size in swine myocardium. Experiments were performed in pentobarbitone-anaesthetized, open-chest pigs which were subjected to a 60 min occlusion of the left anterior descending coronary artery (LADCA) followed by 2 h of reperfusion. Three groups of animals were studied. In the pre-reperfusion group (pre-REP, n = 7) HOE 694 infusion (7 mg/kg/15 min) was started at 45 min of occlusion of the LADCA and continued until the end of occlusion, while in pre-occlusion group (pre-TCO, n = 7) HOE 694 infusion was started 15 min before occlusion and stopped at the onset of ischaemia. In the control group ( n = 7) animals received vehicle alone. At the end of the protocol, infarct size (as d% of the left ventricular risk region) was determined by the p -nitroblue tetrazolium method. Treatment with HOE 694 prior to the ischaemic insult or upon reperfusion significantly reduced infarct size [4.1%(1.4%), P < 0.01 and 38.2%(5.8%), P < 0.05, respectively], compared with 77.7%(4.0%) in the control group. However, infarct size was significantly more reduced in the pre-TCO group than in the pre-REP group ( P < 0.05). Conclusion: Treatment with HOE 694 leads to a significant reduction in infarct size, even when administered after the onset of ischaemia. Thus, inhibition of Na+/H+ exchange was able to limit cell necrosis. This implicates an important role for Na+/H+ exchange in the pathogenesis of infarct expansion and provides evidence that reperfusion injury exists. However, HOE 694 was even more effective when given before ischaemia, indicating an additional protective effect during ischaemia which might be due to slowing down of a vicious cycle that consumes ATP and generates H+. Minimize